Introduction:

Tumor cells are very crafty. They undergo a number of changes to acquire traits beneficial for their survival, a result that is detrimental to the host. Tumor cells exhibit aberrant regulation at multiple levels – including deregulated signal transduction, genetic and epigenetic pathways, and altered metabolism. In many instances, cancer cells demonstrate the coordinated deregulation of several of these mechanisms. Many of these deregulated events reflect the inappropriate activation of pathways normally observed in instance of injury or development. One common example of this is the ability of tumor cells to activate a genetic program termed the epithelial to mesenchymal transition, or EMT. Normal epithelial cells appear square or cuboidal in nature. They are tightly associated with their neighboring cells through adherens junctions, as well as additional junctional and protein-protein interactions. E-cadherin is a main component of adherens junctions, and serves as the ‘glue’ that supports cell-cell contact.

Increased cell motility is a hallmark of tumor cells. The acquisition of this behavior coincides with the loss of E-cadherin, an event that is also a key initiating event for activation of the EMT program. Thus, E-cadherin is a tumor suppressor in part due to its ability to serve as a ‘gatekeeper’ of EMT activation. As shown (Fig. 1), a core group of transcription factors (ie Slug, Snail, Twist) are key drivers of EMT events. During EMT, a ‘cadherin switch’ occurs, whereby E-cadherin expression is lost, and N-cadherin expression is increased. EMT-activated cells lose their contact with neighboring cells, become scattered, motile, and exhibit a mesenchymal, or fibroblastic elongated morphology. These cells also acquire proteolytic activity via activation of matrix metalloproteinases (MMPs) that contribute to the invasive activity.

EMT activation is associated with invasive and metastatic activity (Fig. 2). In solid tumors such as prostate cancer, the epithelial cells grow in a deregulation manner, becoming hyperproliferative and filling the lumen. This causes tissue disorganization and negative effects for the patient. In animal models, activation of EMT events transforms the benign proliferative cells and confers invasive activity. This invasive activity is tightly correlated with tumor dissemination, metastasis, and poor patient prognosis. We are investigating the role of eHsp90 as a regulator of tumor cell EMT and invasive behavior. We are using cell-based models, as well as animal xenograft models, and evaluation of patient material, to investigate this connection.